Genotypes and Haplotypes of the Estrogen Receptor α Gene (ESR1) Are Associated With Female-to-Male Gender Dysphoria.

Introduction: Gender dysphoria, a marked incongruence between one's experienced gender and biological sex, is commonly believed to arise from discrepant cerebral and genital sexual differentiation. With the discovery that estrogen receptor beta is associated with female-to-male (FtM) but not with male-to-female (MtF) gender dysphoria, and given estrogen receptor a involvement in central nervous system masculinization, it was hypothesized that estrogen receptor a, encoded by the ESR1 gene, also might be implicated. Aim: To investigate whether ESR1 polymorphisms (TA) n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 and their haplotypes are associated with gender dysphoria in adults. Methods: Molecular analysis was performed in peripheral blood samples from 183 FtM subjects, 184 MtF subjects, and 394 sex-and ethnically-matched controls. Main Outcome Measures: Genotype and haplotype analyses of the (TA) n-rs3138774, PvuII-rs2234693, and XbaI-rs9340799 polymorphisms. Results: Allele and genotype frequencies for the polymorphism XbaI were statistically significant only in FtM vs control XX subjects (P = .021 and P = .020). In XX individuals, the A/G genotype was associated with a low risk of gender dysphoria (odds ratio [ OR] = 0.34; 95% CI = 0.16-0.74; P = .011); in XY individuals, the A/A genotype implied a low risk of gender dysphoria (OR = 0.39; 95% CI = 0.17-0.89; P = .008). Binary logistic regression showed partial effects for all three polymorphisms in FtM but not in MtF subjects. The three polymorphisms were in linkage disequilibrium: a small number of TA repeats was linked to the presence of PvuII and XbaI restriction sites (haplotype S-T-A), and a large number of TA repeats was linked to the absence of these restriction sites (haplotype L-C-G). In XX individuals, the presence of haplotype L-C-G carried a low risk of gender dysphoria (OR = 0.66; 95% CI = 0.44-0.99; P = .046), whereas the presence of haplotype L-C-A carried a high susceptibility to gender dysphoria (OR = 3.96; 95% CI = 1.04-15.02; P = .044). Global haplotype was associated with FtM gender dysphoria (P = .017) but not with MtF gender dysphoria. Conclusions: XbaI-rs9340799 is involved in FtM gender dysphoria in adults. Our findings suggest different genetic programs for gender dysphoria in men and women. Copyright (C) 2016, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.